A STUB1-CHIC2 complex inhibits CD8+ T cells to restrain tumor immunity

In vivo CRISPR screens in CD8+ T cells have previously uncovered targets for cancer immunotherapy; however, a minority of the genome has been individually annotated, suggesting additional regulators remain to be discovered. Here we assessed 899 genes in CD8+ T cells responding to murine melanoma and identified the E3 ubiquitin ligase STUB1 as a novel negative regulator of anti-tumor CD8+ T cell function. We demonstrated that Stub1 knockout CD8+ T cells effectively control tumor growth across multiple murine models. Mechanistically, STUB1 interacts with the adapter protein CHIC2 to regulate cytokine receptor expression in mouse and human CD8+ T cells. Among the regulated cytokine receptors, IL-27Ra is essential for tumor growth control mediated by Stub1 or Chic2 knockout CD8+ T cells. Together, these findings establish the STUB1-CHIC2 complex as a novel regulator of cytokine receptor expression in CD8+ T cells and provide rationale for inhibiting this pathway to enhance CD8+ T cell-mediated anti-tumor immunity.